Immune defense against new or evolving pathogens is compromised in old age, and this is accompanied by profound defects in T-cell immunity. Improving T-cell function usually restores immune defense in aged animals, arguing that T-cell defects play a key role in immune aging. Latent persisting viral infections were associated with marked T-cell dysregulation in the elderly and also with increased mortality in the advanced age, raising the possibility that the latent viruses from the herpesvirus family may be amongst the key contributors to the age-related decline of the immune system. Despite these provocative possibilities, the role of these viruses in immune senescence remains speculative. This application will investigate whether and how infections with latent herpesviruses contribute to T-cell aging and impair or benefit the immune defense. The two viruses to be used are ubiquitously present in humans and our results and data from literature show that they sculpt much of T-cell repertoire. Therefore, we shall employ a model in which we will induce latent persistent infection in mice, to mimic aspects of human T-cell senescence. We will define, using a reductionist approach, the features of T-cell aging and infectious disease susceptibility that are driven by loss of T-cell diversity and aberrant memory maintenance associated with latent viral infections. Specific aims are: SA1. To elucidate virus and host mechanisms that cause T-cell dysregulation. The roles of viral antigen (Ag), of virus-induced cytokines and of the failure of the aging immune system to eliminate the source of viral Ag (providing extended T-cell stimulation) in precipitating T-cell dysregulation will be addressed SA2. To define the impact of latent viruses upon T-cell repertoire, CD8 T-cell immunity and immune defense in aging. Both the diversity of naive CD8 T-cells and the ability to respond to new pathogenic challenge is reduced in aging and this aim will test whether these important T-cell functions are further compromised by lifelong herpesvirus infections. Because latent herpesvirus infections were recently shown to be beneficial to the host by cross-protecting against certain bacteria, the aim will also test whether such beneficial effects extend to the old age. The above experiments will establish the overall impact of latent herpesviruses upon the host immunity over the lifespan and will provide insights into points of potential intervention against immune aging and age-related vulnerability to infectious diseases. PUBLIC HEALTH RELEVANCE: In a model mimicking human aging, this application will seek to elucidate the mechanisms by which latent herpesviruses affect immunosenescence and pathogen susceptibility, and thus provide new basic insights into virus:T-cell relationship in aging and into potential treatments of age-related T-cell disorders.